Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

Kevin Pethe; Pablo Bifani; Jichan Jang; Sunhee Kang; Seijin Park; Sujin Ahn; Jan Jiricek; Juyoung Jung; Hee Kyoung Jeon; Jonathan Cechetto; Thierry Christophe; Honggun Lee; Marie Kempf; Mary Jackson; Anne J. Lenaerts; Ha Pham; Victoria Jones; Min Jung Seo; Young Mi Kim; Mooyoung Seo; Jeong Jea Seo; Dongsik Park; Yoonae Ko; Inhee Choi; Ryangyeo Kim; Se Yeon Kim; Seungbin Lim; Seung Ae Yim; Jiyoun Nam; Hwankyu Kang; Haejin Kwon; Chun Taek Oh; Yoojin Cho; Yunhee Jang; Junghwan Kim; Adeline Chua; Bee Huat Tan; Mahesh B. Nanjundappa; Srinivasa P.S. Rao; Whitney S. Barnes; René Wintjens; John R. Walker; Sylvie Alonso; Saeyeon Lee; Jungjun Kim; Soohyun Oh; Taegwon Oh; Ulf Nehrbass; Sung Jun Han; Zaesung No; Jinhwa Lee; Priscille Brodin; Sang Nae Cho; Kiyean Nam; Jaeseung Kim

doi:10.1038/nm.3262

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

Kevin Pethe^*, Pablo Bifani, Jichan Jang, Sunhee Kang, Seijin Park, Sujin Ahn, Jan Jiricek, Juyoung Jung, Hee Kyoung Jeon, Jonathan Cechetto, Thierry Christophe, Honggun Lee, Marie Kempf, Mary Jackson, Anne J. Lenaerts, Ha Pham, Victoria Jones, Min Jung Seo, Young Mi Kim, Mooyoung SeoJeong Jea Seo, Dongsik Park, Yoonae Ko, Inhee Choi, Ryangyeo Kim, Se Yeon Kim, Seungbin Lim, Seung Ae Yim, Jiyoun Nam, Hwankyu Kang, Haejin Kwon, Chun Taek Oh, Yoojin Cho, Yunhee Jang, Junghwan Kim, Adeline Chua, Bee Huat Tan, Mahesh B. Nanjundappa, Srinivasa P.S. Rao, Whitney S. Barnes, René Wintjens, John R. Walker, Sylvie Alonso, Saeyeon Lee, Jungjun Kim, Soohyun Oh, Taegwon Oh, Ulf Nehrbass, Sung Jun Han, Zaesung No, Jinhwa Lee, Priscille Brodin, Sang Nae Cho, Kiyean Nam, Jaeseung Kim

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

480 Citations (Scopus)

Abstract

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide^1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis^3-5, several of which are currently in clinical trials^6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

Original language	English
Pages (from-to)	1157-1160
Number of pages	4
Journal	Nature Medicine
Volume	19
Issue number	9
DOIs	https://doi.org/10.1038/nm.3262
Publication status	Published - Sept 2013
Externally published	Yes

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Pethe, K., Bifani, P., Jang, J., Kang, S., Park, S., Ahn, S., Jiricek, J., Jung, J., Jeon, H. K., Cechetto, J., Christophe, T., Lee, H., Kempf, M., Jackson, M., Lenaerts, A. J., Pham, H., Jones, V., Seo, M. J., Kim, Y. M., ... Kim, J. (2013). Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine, 19(9), 1157-1160. https://doi.org/10.1038/nm.3262

@article{9af3fd414507432690cfe76ec074c053,

title = "Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis",

abstract = "New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3-5, several of which are currently in clinical trials6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.",

author = "Kevin Pethe and Pablo Bifani and Jichan Jang and Sunhee Kang and Seijin Park and Sujin Ahn and Jan Jiricek and Juyoung Jung and Jeon, {Hee Kyoung} and Jonathan Cechetto and Thierry Christophe and Honggun Lee and Marie Kempf and Mary Jackson and Lenaerts, {Anne J.} and Ha Pham and Victoria Jones and Seo, {Min Jung} and Kim, {Young Mi} and Mooyoung Seo and Seo, {Jeong Jea} and Dongsik Park and Yoonae Ko and Inhee Choi and Ryangyeo Kim and Kim, {Se Yeon} and Seungbin Lim and Yim, {Seung Ae} and Jiyoun Nam and Hwankyu Kang and Haejin Kwon and Oh, {Chun Taek} and Yoojin Cho and Yunhee Jang and Junghwan Kim and Adeline Chua and Tan, {Bee Huat} and Nanjundappa, {Mahesh B.} and Rao, {Srinivasa P.S.} and Barnes, {Whitney S.} and Ren{\'e} Wintjens and Walker, {John R.} and Sylvie Alonso and Saeyeon Lee and Jungjun Kim and Soohyun Oh and Taegwon Oh and Ulf Nehrbass and Han, {Sung Jun} and Zaesung No and Jinhwa Lee and Priscille Brodin and Cho, {Sang Nae} and Kiyean Nam and Jaeseung Kim",

note = "Funding Information: This work was supported by a National Research Foundation of Korea grant funded by the Korean government Ministry of Education, Science and Technology (2012-00011), the Korea Institute of Science and Technology Information, Gyeonggi-do and Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale-Avenir. R.W. received support from the Belgian Fund for Scientific Research. We thank T. Diagana and P. Smith for critical reading of the manuscript.",

year = "2013",

month = sep,

doi = "10.1038/nm.3262",

language = "English",

volume = "19",

pages = "1157--1160",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "9",

}

Pethe, K, Bifani, P, Jang, J, Kang, S, Park, S, Ahn, S, Jiricek, J, Jung, J, Jeon, HK, Cechetto, J, Christophe, T, Lee, H, Kempf, M, Jackson, M, Lenaerts, AJ, Pham, H, Jones, V, Seo, MJ, Kim, YM, Seo, M, Seo, JJ, Park, D, Ko, Y, Choi, I, Kim, R, Kim, SY, Lim, S, Yim, SA, Nam, J, Kang, H, Kwon, H, Oh, CT, Cho, Y, Jang, Y, Kim, J, Chua, A, Tan, BH, Nanjundappa, MB, Rao, SPS, Barnes, WS, Wintjens, R, Walker, JR, Alonso, S, Lee, S, Kim, J, Oh, S, Oh, T, Nehrbass, U, Han, SJ, No, Z, Lee, J, Brodin, P, Cho, SN, Nam, K & Kim, J 2013, 'Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis', Nature Medicine, vol. 19, no. 9, pp. 1157-1160. https://doi.org/10.1038/nm.3262

TY - JOUR

T1 - Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

AU - Pethe, Kevin

AU - Bifani, Pablo

AU - Jang, Jichan

AU - Kang, Sunhee

AU - Park, Seijin

AU - Ahn, Sujin

AU - Jiricek, Jan

AU - Jung, Juyoung

AU - Jeon, Hee Kyoung

AU - Cechetto, Jonathan

AU - Christophe, Thierry

AU - Lee, Honggun

AU - Kempf, Marie

AU - Jackson, Mary

AU - Lenaerts, Anne J.

AU - Pham, Ha

AU - Jones, Victoria

AU - Seo, Min Jung

AU - Kim, Young Mi

AU - Seo, Mooyoung

AU - Seo, Jeong Jea

AU - Park, Dongsik

AU - Ko, Yoonae

AU - Choi, Inhee

AU - Kim, Ryangyeo

AU - Kim, Se Yeon

AU - Lim, Seungbin

AU - Yim, Seung Ae

AU - Nam, Jiyoun

AU - Kang, Hwankyu

AU - Kwon, Haejin

AU - Oh, Chun Taek

AU - Cho, Yoojin

AU - Jang, Yunhee

AU - Kim, Junghwan

AU - Chua, Adeline

AU - Tan, Bee Huat

AU - Nanjundappa, Mahesh B.

AU - Rao, Srinivasa P.S.

AU - Barnes, Whitney S.

AU - Wintjens, René

AU - Walker, John R.

AU - Alonso, Sylvie

AU - Lee, Saeyeon

AU - Kim, Jungjun

AU - Oh, Soohyun

AU - Oh, Taegwon

AU - Nehrbass, Ulf

AU - Han, Sung Jun

AU - No, Zaesung

AU - Lee, Jinhwa

AU - Brodin, Priscille

AU - Cho, Sang Nae

AU - Nam, Kiyean

AU - Kim, Jaeseung

N1 - Funding Information: This work was supported by a National Research Foundation of Korea grant funded by the Korean government Ministry of Education, Science and Technology (2012-00011), the Korea Institute of Science and Technology Information, Gyeonggi-do and Institut National de la Santé et de la Recherche Médicale-Avenir. R.W. received support from the Belgian Fund for Scientific Research. We thank T. Diagana and P. Smith for critical reading of the manuscript.

PY - 2013/9

Y1 - 2013/9

N2 - New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3-5, several of which are currently in clinical trials6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

AB - New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3-5, several of which are currently in clinical trials6-8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

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U2 - 10.1038/nm.3262

DO - 10.1038/nm.3262

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VL - 19

SP - 1157

EP - 1160

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

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